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Blood, 1 October 2004, Vol. 104, No. 7, pp. 1931-1939.
Prepublished online as a Blood First Edition Paper on May 27, 2004; DOI 10.1182/blood-2004-01-0246.
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Submitted January 21, 2004
Accepted May 9, 2004
Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders
Animesh Pardanani and Ayalew Tefferi*
Hematology, Mayo Clinic, Rochester, MN, USA
* Corresponding author; email: tefferi.ayalew{at}mayo.edu.
Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet derived growth factor receptor (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of a similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33 and the latter from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, both in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, both wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.
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